Redefining first-line standards: The role of next-generation HER2-Targeted therapies in HER2-positive metastatic breast cancer.

The combination of trastuzumab, pertuzumab, and taxane (THP) has been the cornerstone of the first-line treatment for human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (mBC) since the CLEOPATRA trial. However, this long-standing paradigm is now being redefined by compelling evidence from practice-changing trials. Recent advances are challenging THP's dominance with impressive clinical activity across multiple trials evaluating anti-HER2 antibody-drug conjugates (ADC) and CDK4/6 inhibitors. The DESTINY-Breast09 (DB09) trial established superiority of the ADC trastuzumab deruxtecan (T-DXd) combined with pertuzumab over THP, positioning chemotherapy-free strategies as potential new standards. For patients with HR+/HER2+ disease, the PATINA study extends the first-line strategy by demonstrating that adding a CDK4/6 inhibitor as maintenance therapy significantly improves outcomes for patients with HR+/HER2+ disease who have completed initial THP induction. This review comprehensively summarizes the evolution of first-line treatment strategies for HER2+ mBC and critically evaluates clinical evidence from pivotal trials, including emerging evidence in first-line treatments and new agents with potential first-line applications. Challenges, including drug resistance mechanisms, optimal treatment sequencing, and management of special populations, are also discussed.